Microneedle structure and production method therefor

ABSTRACT

A method for processing a wafer to form a plurality of hollow microneedles projecting from a substrate includes forming, by use of a dry etching process, a number of groups of recessed features, each including at least one slot deployed to form an open shape having an included area and at least one hole located within the included area. The internal surfaces of the holes and the slots are then coated with a protective layer. An anisotropic wet etching process is then performed in such a manner as to remove material from outside the included areas while leaving a projecting feature within each of the included areas. The protective layer is then removed to reveal the microneedles.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to microneedle structures and, inparticular, it concerns a microneedle production method and themicroneedle structure produced thereby.

Much research has been directed towards the development of microneedlesformed on chips or wafers by use of micro-machining techniques. Thisapproach promises the possibility of producing numerous, very smallneedles which are sufficient to form small perforations in the dermalbarrier, thereby overcoming the molecular size limitations ofconventional transdermal patches, while being safe for use byunqualified personnel. Examples of such work may be found in PCTPublication No. WO 99/64580 to Georgia Tech Research Corp., as well asin the following scientific publications: “Micro machined needles forthe transdermal delivery of drugs”, S. H. S. Henry et al. (MEMS 98,Heildelberg, Germany, January 1998); “Three dimensional hollow microneedle and microtube arrays”, D. V. McAllister et al. (Transducer 99,Sendai, Japan, June 1999); “An array of hollow micro-capillaries for thecontrolled injection of genetic materials into animal/plant cells”, K.Chun et al. (MEMS 99, Orlando, Fla., January 1999); and “Injection ofDNA into plant and animal tissues with micromechanical piercingstructures”, W. Trimmer et al. (IEEE workshop on MEMS, Amsterdam,January 1995). The more recent of these references, namely, the GeorgiaTech application and the Chun et al. reference, disclose the use ofhollow microneedles to provide a flow path for fluid flow through theskin barrier.

While hollow microneedles are potentially an effective structure fordelivering fluids across the dermal barrier, the structures proposedto-date suffer from a number of drawbacks. Most notably, the proposedstructures employ microneedles with flat hollow tips which tend to puncha round hole through the layers of skin. This punching action tends tocause damage to the skin. Additionally, the punched material tends toform a plug which at least partially obstructs the flow path through themicroneedle. This is particularly problematic where withdrawal of fluidsis required since the suction further exacerbates the plugging of thehollow tube within the microneedle. The flat ended form of the needlesalso presents a relatively large resistance to penetration of the skin,reducing the effectiveness of the structure.

A further group of proposed devices employ microneedles formed byin-plane production techniques. Examples of such devices are describedin U.S. Pat. No. 5,591,139 to Lin et al., U.S. Pat. No. 5,801,057 toSmart et al., and U.S. Pat. No. 5,928,207 to Pisano et al. The use ofin-plane production techniques opens up additional possibilities withregard to the microneedle tip configuration. This, however, is at thecost of very limited density of microneedles (either a singlemicroneedle, or at most, a single row of needles), leading tocorresponding severe fluid flow rate limitations. The very long proposedneedle (about 3 mm) of Smart et al. suffers from an additional very highrisk of needle breakage.

Co-pending U.S. patent application Ser. No. 09/589,369, which isunpublished at the date of filing this application and which does notconstitute prior art, proposes an improved out-of-plane hollowmicroneedle structure having an aperture which is located behind anon-hollow piercing tip. The application describes a number ofproduction techniques for such structures, including techniques basedupon either dry etching or by combining wet etching techniques withasymmetric abrasion.

While the techniques described in the aforementioned co-pendingapplication produce highly effective microneedle structures, variousdisadvantages are encountered while implementing such techniques incommercial production. Firstly, conventional deep reactive ion etching(DRIE) is generally sufficiently inaccurate to reduce the usable yieldto unacceptably low proportions. Accuracy can be greatly improved byusing cryogenic dry etching techniques. This option, however, greatlyreduces the rate at which material can be etched away. As a result,these techniques are inefficient for processing large areas of a wafer.Wet techniques, on the other hand, are efficient for simultaneousprocessing of large regions of a wafer and offer high accuracy. Wettechniques are not, however, suited for directly achieving theasymmetrical forms required for implementation of the microneedles.

A further shortcoming of microneedle structures made by micromachiningtechniques is the brittleness of the resulting microneedles.Microneedles made from silicon or silicon dioxide are highly brittle. Asa result, a significant proportion of the microneedles may fracture dueto the stresses occurring during penetration, leaving fragments of thematerial within the tissue. Furthermore, oblique insertion by anunskilled person could lead to fracture of a very large proportion ofthe needles, resulting in malfunction of the device.

There is therefore a need for a method for producing hollow microneedleswhich would combine the advantages of dry and wet etching techniques tooffer an effective and reliable production technique. It would also behighly advantageous to provide microneedle structures produced by suchproduction methods.

SUMMARY OF THE INVENTION

The present invention is a method for producing hollow microneedlesusing a sequence of dry and wet etching techniques, and a hollowmicroneedle structure produced by such techniques.

According to the teachings of the present invention there is provided, amethod for processing a wafer to form a plurality of hollow microneedlesprojecting from a substrate, the method comprising the steps of: (a)forming by use of a dry etching process a plurality of groups ofrecessed features, each group of recessed features including at leastone slot deployed to form an open shape having an included area and atleast one hole located within the included area; (b) coating internalsurfaces of the holes and the slots with a protective layer; (c)performing an anisotropic wet etching process in such a manner as toremove material from outside the included areas while leaving aprojecting feature within each of the included areas; and (d) removingthe protective layer.

According to a further feature of the present invention, the open shapeis substantially a V-shape formed from two substantially straight slots.

According to a further feature of the present invention, the V-shape ismodified by a minimum radius of curvature at the intersection of the twosubstantially straight slots.

According to a further feature of the present invention, the twosubstantially straight slots subtend an angle of between about 60° andabout 120° therebetween.

According to a further feature of the present invention, the twosubstantially straight slots subtend an angle of between about 85° andabout 95° therebetween.

According to a further feature of the present invention, the dry etchingprocess employs deep reactive ion etching.

According to a further feature of the present invention, the dry etchingprocess includes cryogenic dry etching.

According to a further feature of the present invention, a minimumtransverse dimension of the hole is greater than a minimum transversedimension of the slots such that the hole extends to a depth greaterthan the slots.

According to a further feature of the present invention, a plurality ofconnecting holes are formed penetrating into a face of the waferopposite to the projections such that the each of the connecting holesinterconnects with a corresponding one of the holes to form a throughchannel for fluid flow.

According to a further feature of the present invention, the wet etchingprocess employs a solution containing potassium hydroxide.

According to a further feature of the present invention, the wet etchingprocess is performed in such a manner as to selectively remove materialfrom within the included areas such that each of the projecting featuresexhibits an inclined upper surface sloping upward from the substrate.

There is also provided according to the teachings of the presentinvention, a microneedle structure integrally formed so as to projectfrom a surface of a wafer, the surface corresponding substantially to a<100> crystallographic plane, the microneedle structure comprising: (a)at least one wall standing substantially perpendicular to the wafersurface; (b) an inclined surface corresponding to a crystallographicplane and extending from the wafer surface to an intersection with theat least one wall; and (c) a fluid flow channel extending from theinclined surface through to an opposing face of the wafer.

According to a further feature of the present invention, the at leastone wall includes at least two substantially straight wall portionstogether forming a V-shape.

According to a further feature of the present invention, the at leastone wall further includes a curved portion interconnecting the at leasttwo substantially straight wall portions.

According to a further feature of the present invention, the twosubstantially straight wall portions subtend an angle of between about60° and about 120° therebetween.

According to a further feature of the present invention, the twosubstantially straight wall portions subtend an angle of between about85° and about 95° therebetween.

According to a further feature of the present invention, the inclinedsurface corresponds substantially to a <111> crystallographic plane.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings, wherein:

FIGS. 1A-1D are schematic isometric views illustrating four stages of amethod for producing hollow microneedles according to the teachings ofthe present invention;

FIGS. 2A-2F are schematic cross-sectional views illustrating more fullythe method of FIGS. 1A-1D;

FIGS. 3A-3D are plan views of a number of alternative slot forms whichmay be used to implement the method of the present invention;

FIG. 4 is an enlarged isometric view of an array of hollow microneedlesformed by the method of the present invention of a wafer surface;

FIG. 5 is a further enlarged isometric view of one of the microneedlesfrom FIG. 4; and

FIG. 6 is an enlarged isometric view of an array of a second form ofhollow microneedles formed by the method of the present invention of awafer surface.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is a method for producing hollow microneedlesusing a sequence of dry and wet etching techniques, and a hollowmicroneedle structure produced by such techniques.

The principles and operation of production techniques and the resultingstructures according to the present invention may be better understoodwith reference to the drawings and the accompanying description.

Turning now to the drawings, FIGS. 1A-1D and 2A-2F illustrateschematically a method for processing a wafer 10 to form a plurality ofhollow microneedles 12 projecting from a substrate 14.

Generally speaking, the method first employs a dry etching process toform a plurality of groups of recessed features, each group of recessedfeatures including at least one slot 16 deployed to form an open shapehaving an included area 18 and at least one hole 20 located withinincluded area 18. One such group of features is shown in FIGS. 1A and2A.

Internal surfaces of holes 20 and slots 16 are then coated with aprotective layer 22 (FIGS. 1B and 2D) prior to performing an anisotropicwet etching process to remove material substantially uniformly fromoutside included areas 18 while leaving a projecting feature,corresponding to microneedles 12, within each included area 18. Thisstage is shown in FIGS. 1C and 2E. Protective layer 22 is then removed,leaving microneedles 12 projecting from the surface of the substrate 14(the remaining thickness of the initial wafer 10), as shown in FIGS. 1Dand 2F.

It will be immediately appreciated that this process offers a highlyefficient and reliable production technique for hollow microneedles.Specifically, since the volume of material to be removed by the dryetching process is small, highly accurate techniques, such as cryogenicDRIE, may be used to advantage without unduly lengthening the productiontime. The subsequent use of wet etching techniques then allows largervolumes of material to be removed quickly and accurately to achieve ahigh yield finished product. The structure of the resulting microneedlesis highly robust and may be used to advantage for transdermal drugdelivery and/or diagnostic sampling, for example, as part of the devicesand systems described in the aforementioned U.S. patent application Ser.No. 09/589,369, which is hereby incorporated by reference. This andother advantageous of the method and corresponding structures of thepresent invention will be better understood from the following moredetailed description.

Before turning to the features of the present invention in more detail,it will be helpful to clarify certain terminology as it is to be usedthroughout the description and claims. Firstly, the terms “dry etchingprocess” and “wet etching process” are used according to their acceptedusage to refer to etching processes in which the primary etching step isperformed by exposure to a solution (“wet”) or by other means (“dry”).Clearly, these terms do not exclude the use of additional preparatory orsubsequent “dry” processing steps in a wet etching process, or viceversa.

The term “wafer” is used herein to refer to the material from which themicroneedles are to be formed. Typically, the wafers used are singlecrystal wafers, most preferably of cubic structure such as silicon. Theterm “substrate” is used for the underlying structure upon which themicroneedles are supported. Clearly, the substrate thus defined isgenerally a remaining thickness of the original wafer after completionof the processing.

The term “microneedle” is used herein to refer to a projection formed ona surface of a substrate. For transdermal fluid transfer applications,microneedles are configured to project to a maximum height above thesubstrate of no more than 2 mm, and typically no more than 500 μm.Further details of the design considerations in choosing dimensions ofthe microneedles for various applications are discussed in theaforementioned co-pending application and will not be dealt with here.

The term “hollow” is used to refer to a microneedle structure throughwhich a fluid flow conduit passes, in contrast to a “solid microneedle”which lacks such a conduit. It should be noted that the conduit istypically a small proportion of the volume of the microneedleprojection.

Finally, use will be made herein of various geometric terminology.Specifically, the term “open shape” is used to refer to a shape formedby one or more contiguous line which does not close on itself. Despitethis lack of closure, reference is made to an “enclosed area” defined bythe open shape. This enclosed area is defined to be the largestcontiguous area which can be enclosed by adding a single straight lineto the open shape. The open shape is chosen such that the enclosed areais non-zero, i.e., it is not a single straight line.

Turning now to the features of the present invention in more detail, thevarious stages of a preferred implementation of the production processwill be described with reference to FIGS. 2A-2F.

Firstly, FIG. 2A shows wafer 10 after the dry etching process.Preferably, as mentioned above, high accuracy is achieved by usingcryogenic DRIE or other high-accuracy dry etching processes. The waferis first prepared, as is known in the art, by cleaning followed bylithography to prepare a mask for the DRIE. Preferably, a minimumtransverse dimension of hole 20 is greater than a minimum transversedimension of slots 16. As a result, hole 20 is etched at a slightlygreater rate than slot 16, so that the hole extends to a greater depth.Typical values for the width of slots 16 are in the range of about 10 toabout 20 microns. The dimensions of hole 20 are generally in the rangeof 20-150 micron, chosen as a function of the dimensions of themicroneedles to be produced.

Referring briefly to FIGS. 3A-3D, it should be noted that a wide rangeof different configurations may be used for the open shape formed byslot(s) 16. In one preferred example shown in FIG. 3A, the open shape isa V-shape formed from two substantially straight slots 16 a and 16 b.FIG. 3B shows a more preferred example where the V-shape is modified bya curved connecting slot 16 c having a given minimum radius of curvatureat the intersection of the two substantially straight slots 16 a and 16b. This minimum radius of curvature preferably has a value in the rangeof about 5 μm to about 100 μm, and most preferably in the range of 10-50μm. The latter shape is believed to result in a more robust microneedletip. In both cases, slots 16 a and 16 b preferably subtend an angle ofbetween about 60° and about 120°, and more preferably between about 85°and about 95°, therebetween.

Although the aforementioned slot shapes are believed to be preferred, itshould be noted that a wide range of other forms are also effective andmay, in some cases, offer certain advantages. By way of example, FIG. 3Cshows a slot configuration similar to FIG. 3B in which curved slot 16 cis replaced by a third straight slot 16 d. FIG. 3D shows a furtherexample where the entire slot 16 is implemented as a single graduatedcurved form approximating to a U-shape.

It will be noted that the choice of open shape formed by slot(s) 16 andits orientation with respect to the crystal axes must be chosen inaccordance with the intended wet etch process so as to form the requiredprojecting microneedle. By way of example, in the case of the preferredKOH etch, the open shape must be sufficiently enclosed to inhibit therapid etching of the <100> plane within the contained area, therebyallowing the required microneedle structure to form by etching of the<111> plane which occurs much more slowly in KOH. To form a symmetricalmicroneedle, the line that bisects the angle between slots 16 a and 16 bshould be perpendicular to a <110> plane. In a most preferred exampleillustrated herein, the slots correspond substantially to two <100>planes.

The length dimensions of slot 16 are chosen according to the size ofmicroneedle required.

Hole 20 also may vary in shape. In some cases, a circular hole may bepreferred. An asymmetric hole, typically roughly elliptical, is oftenmore advantageous, allowing an increase of the cross-section (and henceflow capacity) of the hole without coming overly close to slots 16.Optionally, other forms, such as a hole approximating to a triangularform, could be used to achieve similar results.

Turning now to FIG. 2B, it is a particularly preferred feature of theprocess and structure of the present invention that holes 20 areconnected in fluid flow connection with the rear surface 24 of substrate14 to allow fluid transfer via microneedles 12. To this end, a pluralityof connecting holes 26 are preferably formed, penetrating into surface24 such that each of connecting hole 26 interconnects with acorresponding hole 20 to form a through channel.

Connecting holes 26 are typically formed by back-side processing similarto that used for holes 20 and slots 16 on the front-side of the wafer.Precautions must be taken to ensure proper alignment of the front-sideand back-side masks, as is known in the art. The tolerance of thealignment is preferably increased slightly by employing connecting holes26 of diameter greater than the dimensions of front-side holes 20. Theconnecting holes are preferably centered slightly further away fromslots 16 in order to avoid accidental perforation of the substrate viathe slots. The depth differential between holes 20 and slots 16 providesan additional safeguard against this problem.

The order of processing of the front and back surfaces of the wafer isgenerally not critical, and depends primarily on practical logisticalconsiderations. Thus, the back-side processing can be performed prior toany front-side processing, or between the dry and wet etching steps.Typically, however, the back-side processing should be performed priorto the wet etching step in order to avoid damage to the microneedleswhich are then formed on the front surface. Additionally, it may beadvantageous to perform the front-side dry etch first to allow slight“over etching”, i.e., etching to slightly greater than the theoreticalrequired depth to ensure intersection with the back-side holes.

Turning now to FIGS. 2C, 2D and 2E, the choice of material forprotective coating 22 must be suited to the type of wet etch process tobe performed. In a particularly preferred implementation, the wetetching process employs a solution containing potassium hydroxide (KOH).A suitable protective coating material for such an implementation isSiRN. In order to achieve selective coating of the insides of holes 20and slots 16, the coating is typically performed in two steps: first, auniform coating over all exposed surfaces (FIG. 2C), such as by lowpressure chemical vapor deposition (LPCVD); then, selective removal ofthe coating from the upper surface (FIG. 2D), such as by reactive ionetching (RIE), while leaving the coating within the holes and slots.

The anisotropic wet etching process then removes the upper surface ofthe wafer, generally keeping to the <100> horizontal crystallographicplane. Only where the etching process is asymmetrically limited bypartial enclosure within walls formed by protective coating 22, theanisotropic wet etching process adopts alternative crystallographicforms, leading to formation of projections 12 (FIG. 2E). The protectivecoating 22 is then removed, typically by a further wet etching process.In the aforementioned example, the protective coating material iseffectively removed by a hydrogen fluoride (HF) etch.

It will be noted that the pyramid-like structure of the microneedlesproduced by the method of the present invention is generally highlyrobust, thereby greatly reducing the likelihood of fracture during useof the microneedles. This robustness is further enhanced by themodification of the pyramid-like structure to include a rounded-wallconfiguration of FIGS. 1A-1D, 3B and 6. Nevertheless, in certain cases,the resulting structure may optionally be further processed by additionof various coating layers to provide additional desirable properties, aswill now be described.

Firstly, depending upon the wafer material, it may be preferable to coatat least the microneedles with a layer of bio-compatible material,typically a metal or metal alloy. For this purpose, a coating of about 2μm titanium or stainless steel is typically sufficient. Thicker coatingof at least 10-20 μm may also serve a structural safety function,tending to prevent fragments being left behind in the event that abrittle silicon needle might fracture.

According to a further preferred option, a layer of at least about 20 μmof a super-elastic alloy is deposited over at least the conicalprojections. An example of such an alloy is the range of NiTi alloysgenerally known as Nitinol. This offers a still further enhanced levelof structural safety by providing a layer which is not prone to breakingor fracturing under a very wide range of operating conditions.

One preferred technique for forming the aforementioned metallic layersis sputtering. Sputtering techniques for applying NiTi are discussed in“Micromachining Process for thin film SMA actuators”, Nakamura et al.(IEEE, February 1996). In order to achieve the required NiTistoichiometry to produce super elastic properties, it is recommended touse a target such as micro needles pre-coated with a small amount of Tior Ni. Increasing or decreasing the amount of Ni or Ti or any ternaryelement can result in a film transformation which is the basic principleof super alloy properties of any desired composition. The exactcomposition defines the temperature at which the super elastic behavioris exhibited. It has also been demonstrated that adjusting the target tosubstrate distance and sputtering gas pressure can change the NiTistoichiometry from 47% to 52% Ti, while using a 50% Ti target. Suchchanging in the stoichiometry could produce super elastic properties atabout room temperature. The deposited amorphous films must be annealedto achieve crystallinity. This annealing also promotes adhesion to thesubstrate through formation of a thin reaction layer (˜40 nm). Forequi-atomic NiTi , no change of thin film phase transformation asobserved when annealing between 500-700° C., However Ti-rich filmdisplays an increased transformation temperature while Ni-rich filmdisplays a decreased temperature transformation. Thin film can recoverfrom 6% strain at 600 MPa forces which is above the need for microneedleconfigurations.

In yet a further option, at least part of the substrate material isremoved by etching away from under the metallic or super-elastic layerso as to leave the microneedle projections formed substantiallyexclusively from the layer of metallic material or super-elastic alloy.In the most highly preferred case of a super-elastic alloy, this resultsin a microneedle array which is effectively unbreakable under a widerange of conditions. This provides a highly valuable solution to theproblem of fractured microneedles associated with the prior art, andprovides a greatly improved level of safety against damage to the deviceor harm to the user if the needles are inserted improperly at an obliqueangle to the skin.

Although shown here schematically with a single microneedle, the processdescribed is clearly well suited to producing a one- or two-dimensionalarrays of microneedles projecting from the surface of substrate 12 withany desired spacing, layout and dimensions. In fact, it is aparticularly preferred feature of the microneedle structures of thepresent invention that a two-dimensional array including at least 20microneedles is provided. More preferably, at least 50 microneedles areprovided on each chip, and most preferably, at least 100. In manypractical applications, large arrays of several hundreds of microneedlesmay be formed on a chip of less than 1 cm². The spacing between centersof adjacent microneedles in a given direction is typically in the rangeof 2-10 times the maximum dimension of each needle in that direction.

Turning finally to FIGS. 4-6, these illustrate the microneedle structureresulting from the production process described above. Specifically,FIGS. 4 and 5 show an array of microneedles formed from the slot patternof FIG. 3A, while FIG. 6 shows a corresponding array formed using thepattern of FIG. 3B.

In each case, the resulting structure includes an array of microneedlesintegrally formed so as to project from a wafer surface correspondingsubstantially to a <100> crystallographic plane. Each microneedle has atleast one wall standing substantially perpendicular to the wafersurface, an inclined surface corresponding to a crystallographic planeand extending from the wafer surface to an intersection with the atleast one wall, and a fluid flow channel extending from the inclinedsurface through to an opposing face of the wafer. The intersection ofthe fluid flow channel with the inclined surface offers an enlargedopening, thereby enhancing the capabilities of the microneedle for fluidtransfer, and particularly diagnostic sample withdrawal, across a skinbarrier.

In the preferred example described above employing KOH, the inclinedsurface corresponds substantially to a <111> crystallographic plane.

It will be appreciated that the above descriptions are intended only toserve as examples, and that many other embodiments are possible withinthe spirit and the scope of the present invention.

What is claimed is:
 1. A method for processing a wafer to form aplurality of hollow microneedles projecting from a substrate, the methodcomprising the steps of: (a) forming by use of a dry etching process aplurality of groups of recessed features, each group of recessedfeatures including at least one slot deployed to form an open shapehaving an included area and at least one hole located within saidincluded area; (b) coating internal surfaces of said holes and saidslots with a protective layer; (c) performing an anisotropic wet etchingprocess in such a manner as to remove material from outside saidincluded areas while leaving a projecting feature within each of saidincluded areas; and (d) removing said protective layer.
 2. The method ofclaim 1, wherein said open shape is substantially a V-shape formed fromtwo substantially straight slots.
 3. The method of claim 2, wherein saidV-shape is modified by a minimum radius of curvature at the intersectionof said two substantially straight slots.
 4. The method of claim 2,wherein said two substantially straight slots subtend an angle ofbetween about 60° and about 120° therebetween.
 5. The method of claim 2,wherein said two substantially straight slots subtend an angle ofbetween about 85° and about 95° therebetween.
 6. The method of claim 1,wherein said dry etching process employs deep reactive ion etching. 7.The method of claim 1, wherein said dry etching process includescryogenic dry etching.
 8. The method of claim 1, wherein a minimumtransverse dimension of said hole is greater than a minimum transversedimension of said slots such that said hole extends to a depth greaterthan said slots.
 9. The method of claim 8, further comprising forming aplurality of connecting holes penetrating into a face of said waferopposite to said projections such that said each of said connectingholes interconnects with a corresponding one of said holes to form athrough channel for fluid flow.
 10. The method of claim 1, wherein saidwet etching process employs a solution containing potassium hydroxide.11. The method of claim 1, wherein said wet etching process is performedin such a manner as to selectively remove material from within saidincluded areas such that each of said projecting features exhibits aninclined upper surface sloping upward from said substrate.